Moxonidine having the structural formula I
is a new generation centrally acting antihypertensive drug licensed for the treatment of mild to moderate essential hypertension. It may have a role when thiazides, beta-blockers, ACE inhibitors and calcium channel blockers are not appropriate or have failed to control blood pressure. In addition, it demonstrates favourable effects on parameters of the insulin resistance syndrome, apparently independent of blood pressure reduction. It is a selective agonist at the imidazoline receptor subtype 1 (I1). In addition, moxonidine may also promote sodium excretion, improve insulin resistance and glucose tolerance and protect against hypertensive target organ damage, such as kidney disease and cardiac hypertrophy.
Moxonidine was first disclosed by DE2849537A filed in 1979. Nowadays the compound is available as generic drug. The compound was synthesized by reaction of a 4,6-chloro-5-aminopyrimidine component III with 1-acyl-imidazolidin-2-one IV to intermediate II (R=Acetyl: “DMAIA” (IIa)), followed by substitution of one chloro group by a methoxy group using sodium methoxide/methylate (DE2937023A1, U.S. Pat. No. 4,323,570). EP 1982983A describes an optimized process using sodium methoxide/methylate (NaOMe).
The synthesis of Moxonidine according to original route is shown in scheme 1 below. Pyrimidine systems, in general, can be constructed by conversion of a nitrile to a “Pinner salt”, subsequent ammonialysis and finally condensation with a malonic ester, as shown in scheme 2 below.


Many process related improvements followed, particularly in the field of the base employed in the chloro-methoxy substitution step and the reaction conditions in this step. In order to avoid the disadvantageous use of methoxide, EP1873151A for example describes various alkali hydroxides and (bi)carbonates as well as different reaction conditions regarding equivalents, temperature and time. The reactions were performed in methanol and the crude product isolated after addition of water to the reaction mixture, which is necessary to dissolve inorganic salts that are inevitable when using inorganic base. CZ 294649B6 describes the process in presence of K2CO3 or NaHCO3. WO2008073125A1 describes improved conditions for the first step (coupling) together with an impurity arising from this step.
Some other synthetic routes to moxonidine are also known, for example via thioureas and thioisocyanates (DE2849537A, U.S. Pat. No. 5,684,156A, EP1981498A, WO2007090720A2).
Usually, these conditions suffer from the impurity control and bear the risk of inorganic residues in the product. Therefore, an additional purification step is usually required. In EP1873152A, recrystallization in high-boiling solvents was performed. EP1894927A claims the formation of salts of moxonidine (with organic or inorganic acids). Moreover, these salts were utilized for purification of Moxonidine by reaction with a base to liberate the free Moxonidine. EP1894926A1 describes the preparation (crystallization, precipitation) and characterization of three crystalline forms. In most cases moxonidine is prepared from IIa by applying an inorganic base in methanol. Drawbacks of those processes are difficult control of the impurity profile, because of a usually heterogeneous reaction mixture, and the risk of elevated amounts of inorganic impurities in the final product.
It is therefore an object of the present invention to provide a more simple and reliable process for the production of moxonidine.